S4: Switching on and Maintaining Fuel Supply

Question 1

How does a foetus receive its nutrients?

Answer 1

• A foetus in the uterus receives nutrients from the placenta.
• Foetal size is generally preserved relative to intake in humans, so if a mother eats 80% of what she should the baby will still come out the normal size but the mother will lose weight. There needs to be a significant reduction in calories to other to affect growth of foetus.

Question 2

Describe nutrient use of foetus near term

Answer 2

• The foetus will be using around 5g of glucose per kg per day. The important substrates glucose and amino acids will move across the placenta by facilitated diffusion.
• Insulin is really important in the third trimester in the foetus and is the dominant hormone. This is due to hyperplasia of the beta cells of the pancreas that increases insulin levels. This enables the foetus to lay down its fat stores.

Question 3

Describe neonatal metabolic adaptation

Answer 3

• Takes the baby from a foetal, anabolic metabolic state into a neonatal state where the baby must rely on body stores (catabolism) between feeds.
• Catabolic enzymes systems are not needed in utero and must be switched on for this to happen.

Question 4

Difference in main purpose of insulin in adults and foetus

Answer 4

In the adult insulin main role is to control blood glucose and this is controlled tightly. In the foetus insulin mainly works as an anabolic hormone.

Question 5

Role of insulin

Answer 5

Insulins main role is to remove glucose/substrates from the circulation and store it in tissues.

• Increases glucose uptake into muscle, fat and liver.
• Decreases lipolysis (breakdown of fats).
• Decreases amino acid release from muscle.
• Decreases gluconeogenesis in the liver.
• Decreased ketogenesis in the liver.

Question 6

What nutrition does the baby rely on once born?

Answer 6

• Once born the baby relies on breast milk. Only a small amount of milk is available from the breast initially.
  Thus the baby initially intakes colostrum (first milk), but there is very little of this and it is not enough to meet the babies energy requirements. So the baby has to access and survive on their stores.
• The energy requirement for a newborn is about 4-6g of glucose/kg/day. Later the milk available is more nutritious and fatty.

Question 7

Describe demand (energy partitioning) in newborns

Answer 7

The newborn manages demand and manages supply in order to control its metabolism. In terms of demand, the babies brain accounts for the highest proportion of resting energy expenditure. However, the cerebral metabolic rate (CMRglucose) is relatively low at birth and increases as the brain develops. Thus this is management of demand as the brain is demanding less energy.

Question 8

Describe supply of nutrients from energy stores in newborns

Answer 8

• With regards to supply the baby is by weight about 1% glycogen stored in the liver and about 16% fat.
• Preterm infants are skinny as they have missed the last trimester where the fat stores are laid down. The term infant is chubby as they have had these stores laid down to get them through the neonatal metabolic changes.
  After birth, these baby’s rely primarily on fat stores.

Question 9

Describe how the energy stores in foetus can be converted into fuel that can be used

Answer 9

When in the uterus the foetus has no need to convert stores to fuel as it is receiving all its energy substrate (fuel) from the placenta. Rather all this substrate is built up anabolically into stores in the foetus, this is done under insulin. Once born the baby needs to start to access these stores as it is no longer being just given them automatically, therefore it requires catabolic processes. This is done by switching on the catabolic (counter-regulatory) hormones and this is done in the foetus during labour and delivery. Anabolic actions of insulin are opposed by counterregulatory (Catbolic) hormones.

• There is a huge surge of adrenaline during labour in the foetus and this drives the catabolic metabolism.
• There is also a glycogen surge as plasma glucose levels fall at birth. This opposes insulin and activates gluconeogenesis.

Question 10

List some counterregulatory (catabolic) hormones

Answer 10

Glucagon, Adrenaline, Cortisol and Growth hormone

Question 11

What metabolic processes occur during a postnatal fast

Answer 11

A postnatal fast is the period of time after birth where baby is not eating.
The baby will need to utilise stores to provide glucose as an energy source for its tissues. Processes include:
- Gluconeogenesis: The process of synthesising glucose from non-carbohydrate stores, including muscle (amino acids) and fat via substrates such as lactate, pyruvate, alanine and glycerol.
- Ketogenesis: Is the process of production of ketone bodies (act as a fuel) from the breakdown of fat. In the newborn, ketogenesis is a normal part of their metabolism (especially for the brain) whereas in adults high ketogenesis would be indicative of starvation.

Question 12

Structure of fats

Answer 12

Fats are composed of a glycerol backbone attached via ester bonds to fatty acid chains. These fatty acid chains can vary, they can be saturated or unsaturated (double bonds) etc.

Question 13

Describe oxidation of fat

Answer 13

When we breakdown fats , we do so by removing the glycerol and then slicing off the terminal two carbon group sequentially. This gets bound to coenzyme A, giving us lots of acetyl CoA. This process of breaking down the fatty acid chain into two carbon units is beta-oxidation and occurs in the mitochondria of hepatocytes.

Question 14

Describe formation of ketone bodies

Answer 14

The acetyl CoA from the oxidation of fat can then enter into the TCA cycle and be further metabolised as an energy source like glucose. However in the liver the acetyl CoA will be converted into ketone bodies (e.g. beta-hydroxybuterate, acetone).
This production of ketone bodies is what will be done in the baby over the first post-natal days.

Question 15

Describe the fasting (post-absorptive) state of baby

Answer 15

When a baby is born, the baby goes from having uninterrupted nutrition coming across the placenta to then having periods of time with no food and then eating and then no food and then eating. This is normal, but the baby’s body has to make the switch from continuous nutrition to periods of fasting and feeding.
- When fasting substrates are mobilised in the periphery through counter-regulatory hormones (e.g. glucagon) and released into the circulation and insulin is opposed. Fats and glucose can then be used by active tissues. Catecholamines, Cortisol, Glucagon all oppose insulin.
- Fats –> free fatty acids –> acetyl CoA and ketones.
- Amino acids –> released from muscle to be converted into glucose.
- Glucose will be used by obligate glucose users e.g. brain.

Question 16

Describe the fed (post-prandial) state of baby

Answer 16

• After a meal a lot of insulin is released and starts circulating around!
• The infant diet (milk) is about 50% fat and 40% carbohydrate and this is what the baby needs, the carb part comes mostly from the lactose. Breast milk also contains lipase.
• The insulin that is released allows uptake of blood glucose and storage in muscle and adipose tissue and brain. Glucose will also be taken up into the liver and excess converted to glycogen/fat. Glycogen can be used as a rapid access source of energy when required.
• Active tissues like the brain will simply take the glucose from the circulation as its levels will be high.

Question 17

What are the 4 processes of fuel metabolism babies can have problems with during metabolic adaptation to extrauterine life?

Answer 17

1. Where demand exceeds supply.
2. Hyperinsulinism.
3. Counter-regulatory hormone deficiency.
4. Inborn errors of metabolism.

Question 18

Describe issues babies have with high demand low supply

Answer 18

• An extremely small preterm baby has high metabolic demands (as growing fast) but small nutrient stores and no fat stores (unlike term babies).
• The premature baby also has immature intermediary metabolism, this refers to the hormones that regulate enzyme pathways e.g. switching on gluconeogenesis. This is because in the preterm baby these things aren’t required as all nutrition is coming from the mother. Thus none of these metabolic processes are ready to get switched on in the preterm baby.
• The preterm baby cannot be fed (establishment of enteral feeding delayed). If we tried to pour milk down their throat they would vomit it up, instead we use IV nutrition. This is because although the anatomy of the GI tract is there, it doesn’t yet function properly (e.g. gut hormones not working, peristalsis weak). The IV mimics the placental nutrition and gradually the amount of food is built up over time.
• The baby is very good while in the womb at essentially being a parasite and taking the mothers nutrients and minerals e.g. calcium, phosphate.
• In the preterm baby it is a struggle to get these minerals into the baby due to solubility constraints in giving IV and it being of poor conc. in the breast milk, thus they often end up with metabolic bone disease.
• Also poor fat absorption, only about 70% of fat load absorbed as opposed to 100% in adults.

Question 19

Difference between small for gestational age baby and IUGR (intrauterine growth restriction) baby

Answer 19

• Small for gestational age means the unborn baby falls below a certain centile level, however this can still be normal.
• IUGR indicates that a pathological process has taken place while baby was in utero that has led to the baby being smaller than s/he should have been - often insufficient supply of nutrients across the placenta so IUGR is related to placental functioning.

Question 20

Nutritional demands of an IUGR baby

Answer 20

• The IUGR baby has high demand especially the brain, however stores are low in the liver, muscle and fat.
• Due to no body stores–> problems with low blood sugar.

Question 21

3 major causes hyperinsulinaemia in babies

Answer 21

• Gestational diabetes.
• Beckwith wiedemann syndrome.
• Islet cell disregulation.
  Most cases of hypernsulinaemia are transient but need to be death with straight away.

Question 22

Describe how gestational diabetes can cause hyperinsulinaemia in babies

Answer 22

• Babies of a diabetic mother are chubby and large. They have abnormally large fat stores, big shoulder girdle and thighs, this is how we distinguish them from babies that are just big.
• Neonates of diabetic mothers are prone to neonatal macrosomia and hypoglycaemia, the latter can have severe neurological consequences.
• This is due to the infant being exposed to high maternal glucose during gestation, thus the foetus will also have high plasma glucose as it crosses the placenta by facilitated diffusion. As a result there is foetal hyperinsulinism and once born the insulin is still high. This neonatal hyperinsulinism leads to hypoglycaemia as no longer receiving glucose from mother after birth (high level of insulin is inappropriate for level of glucose released). Sufficient ketone bodies can not be made.
• Blood sugar monitoring is a routine procedure to babies from diabetic mothers.
• Note that the degree of macrosomia doesn’t tell us the degree of hypoglycaemia.

Question 23

Describe Beckwith Wiedemann Syndrome

Answer 23

Beckwith Wiedemann Syndrome is an overgrowth disorder, common features include:

• Macroglossia (large tongue).
• Macrosomia.
• Midline abdominal wall defects (exomphalos/omphalocele, umbilical hernia). Note es of chromosomal abnormality high with exomphalos.
• Ear creases or ear puts.
• Hypoglycaemia due to hyperinsulinaemia.

Question 24

Describe islet cell dysregulation syndromes

Answer 24

3. Islet cell dysregulation syndromes are very rare, but nonetheless are a cause of hyperinsulinism.

Question 25

3 major causes of deficiency of counter regulatory hormones in babies

Answer 25

• Congenital adrenal hyperplasia.
• Hypothalamic-pituitary-adrenal insufficiency.
• Waterhouse-Friderichsen Syndrome.

Question 26

Describe congenital adrenal hyperplasia (CAH)

Answer 26

• Congenital adrenal hyperplasia is usually due to 21 hydroxylase deficiency.
• There is production of too much testosterone, leading to virilisation in females.
• Feel for testes to tell if the infant is a boy or girl at birth.
• Very important to pick up, as can result in a salt-wasting crisis due to the lack of aldosterone and cause hyponatraemia.
• Babies may present with hypoglycaemia due to a lack of cortisol, which is one of the counter-regulatory hormones needed for gluconeogenesis and to release glucose when fasting.

Question 27

Describe Hypothalamic-pituitary-adrenal insufficiency

Answer 27

Classically due to septo-optic dysplasia (a congenital malformation affecting optic nerve, pituitary gland etc.)

Question 28

Describe Waterhouse-Friderichsen Syndrome

Answer 28

Adrenal gland failure due to bleeding into the adrenal gland. Severe adrenal haemorrhage with adrenal gland dysfunction secondary to sepsis or hypoxia. More common in older infants.

Question 29

3 major causes of inborn errors of metabolism in babies

Answer 29

There are a variety of causes of neonatal hypoglycaemia due to genetic abnormalities including:

• Glycogen storage diseases (usually type 1).
• Galactosaemia.
• MCAD (medium chain acyl-CoA dehydrogenase deficiency).

Question 30

Describe glycogen storage disease (type 1)

Answer 30

• Glycogen storage disease (type 1) is due to a deficiency of glucose-6-phosphatase responsible for the rate-limiting step in converting G6P to glucose.
• Individual will present with hypoglycaemia during periods of fasting and stress.
• Newborn will present with hypoglycaemia and lactic acidosis, or may not be seen until child older as hepatomegaly (because unable to break down glycogen).

Question 31

Describe galactosaemia

Answer 31

Lactose in milk is broken down to galactose and glucose. The galactose is then broken down to glucose by galactose-1-phosphate uridyl transferase and this is missing in galactosaemia. This leads to increased levels of the toxic metabolite galactose-1-phosphate.
This leads to:
- Hypoglycaemia.
- Jaundice and liver disease.
- Poor feeding and vomiting.
- Cataracts and brain damage.
- E. coli sepsis (particularly common with galactosaemia! So if see a child with this need to rule out galactosaemia). The most common organism causing foetal sepsis: group B streptococcus, second is e coli.